Treatment of Biliary Duct Cancer

ABSTRACT

The present disclosure provides a method of treating a biliary duct cancer, such as cholangiocarcinoma, by administering a therapeutically effective amount of a compound of formula (I), in particular Varlitinib, an enantiomer thereof or a pharmaceutically acceptable salt of any one of the same.

The present disclosure relates to a therapy, for example a monotherapyor combination therapy comprising a type I tyrosine kinase inhibitor forthe treatment of biliary cancer, such as cholangiocarcinoma.

BACKGROUND

There are many cancers that are difficult to treat and although therapyis available, there appears to exist or to come into existence, a degreeof resistance to the therapy. Primary resistance may occur in thatcancer does not responsive to treatment from the outset. Secondary oracquired resistance also occurs quite frequently, which means that atherapy to which the patient seems to respond, at a certain time, losesits efficacy.

There are numerous reasons for resistance, for example some cancers arediscovered at a late stage and/or a simply not responsive to treatment.

Mechanisms by which cancers avoid the therapeutic effect of therapyinclude but are not limited to:

-   -   i) mutations which render the cancer less vulnerable to the        treatment (eg mutation of the site of action of the therapy),    -   ii) active transportation of the drug out of the tumor, for        example by p-glycolation,    -   iii) building up physical defences, for example stroma which        inhibit certain immune responses, and    -   iv) certain cancers develop paths to repair damage caused by        some anti-cancer therapies.

Tumor heterogeneity may also contribute to resistance, where smallsubpopulations of cells may acquire or stochastically already possesssome of the features enabling them to emerge under selective drugpressure. This is a problem that many patients with cancer encounter,and it obviously limits the therapeutic alternatives that are effectiveand worsens the prognosis.

Cancer therapy guidelines describe the sequence of therapies, which arerecommended and in which sequence, so that if a patients show diseaseprogression on the first therapy (“first line”), then a next therapy(“second line”) is recommended, and so on. These therapy recommendationsare based on available scientific data and experience, and illustratethat resistance to one therapy does not exclude that another therapy maybe effective and prolong life or shrink tumor. At a late stage cancersdo not respond and no more avenues of therapy exist, and are thus judgedas completely therapy refractory, unless new therapies can be foundwhich are effective.

Cholangiocarcinoma is a prime example of both primary and secondaryresistance and is considered to be an incurable and a rapidly lethalmalignancy unless both the primary tumor and any metastases can be fullyresected (removed surgically). No curative treatment exists forcholangiocarcinoma except surgery. Unfortunately, most patients haveadvanced stage disease which is inoperable at the time of diagnosis.Patients with cholangiocarcinoma are generally managed—though nevercured—with chemotherapy, radiation therapy, and other palliative caremeasures. These are also used as adjuvant therapies (i.e. post-surgery)in cases where resection has apparently been successful (or nearly so).

In the western hemisphere cholangiocarcinoma is a relatively rareneoplasm that is classified as an adenocarcinoma (a cancer that formsglands or secretes significant amounts of mucins). It has an annualincidence rate of 1-2 cases per 100,000 in the Western world. However,rates of cholangiocarcinoma have been rising worldwide over the pastseveral decades. Furthermore the incidence is higher in Asian countrieswhere it is recognized as a significant problem.

Thus there a huge clinical need for improved therapies to address thelack effective treatment options for patients with biliary cancer.

(R)—N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5,-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine(Varlitinib Example 52 disclosed in WO2005/016346), is a small-moleculepan-HER inhibitor. It has been tested as a monotherapy in phase Iclinical trials of gastric cancer patients. 23 patients, who hadpreviously failed on one or more rounds of chemotherapy, and whereeligible for trastuzumab, each received 500 mg of Varlitinib orallytwice daily (BID) as monotherapy for 28 days. Tumour biopsies takenbefore and after treatment were analysed using immunohistochemistry.Signs of clinical activity included downregulation of signallingpathways responsible for cell proliferation, and a reduction in cellsurvival and cell proliferation in gastric tumours that were eitherco-expressing EGFR and HER2 or that were HER2 amplified.

In further unpublished clinical work some of the cholangiocarcinomapatients who had previously had several lines of therapy which hadfailed at some stage were given Varlitinib monotherapy or Varlitinib incombination with chemotherapy. Varlitinib monotherapy/combinationtherapy showed a surprising level of efficacy in these patients. Inaddition Varlitinib appears to be efficacious and able to overcome bothprimary and secondary resistance in biliary duct cancer.

SUMMARY OF THE DISCLOSURE

Thus there is provided a method of treating a biliary duct cancer byadministering a therapeutically effective amount of a compound offormula (I):

an enantiomer thereof or a pharmaceutically acceptable salt of any oneof same.

Thus in one embodiment there is provided a compound of formula (I) foruse in the treatment of biliary duct cancer.

Also provided is use of a compound of formula (I) in the manufacture ofa medicament for the treatment of biliary duct cancer.

In one embodiment the biliary duct cancer is selected from the groupconsisting of cholangiocarcinoma, gall bladder cancer and a combinationthereof.

In one embodiment there is provided a method of treating acholangiocarcinoma patient by administering a therapeutically effectiveamount of a compound of formula (I) an enantiomer thereof or apharmaceutically acceptable salt of any one of the same.

In one aspect there is provided use of a compound of formula (I) anenantiomer thereof or a pharmaceutically acceptable salt of any one ofthe same in the treatment of cholangiocarcinoma.

Also provided is a compound of formula (I) an enantiomer thereof or apharmaceutically acceptable salt of any one of the same for use in thetreatment of cholangiocarcinoma.

In one aspect there provided use of a compound of formula (I) anenantiomer thereof or a pharmaceutically acceptable salt thereof for themanufacture of a medicament for the treatment of cholangiocarcinoma.

In one embodiment the cholangiocarcinoma is intrahepatic.

In one embodiment the cholangiocarcinoma is extrahepatic.

In one embodiment the biliary duct cancer is in a location selected fromintrahepatic bile ducts, left hepatic duct, right hepatic duct, commonhepatic duct, cystic duct, common bile duct, Ampulla of Vater andcombinations thereof.

In one embodiment the biliary duct cancer is in an intrahepatic bileduct.

In one embodiment the biliary duct cancer is in a left hepatic duct.

In one embodiment the biliary duct cancer is in a right hepatic duct.

In one embodiment the biliary duct cancer is in a common hepatic duct.

In one embodiment the biliary duct cancer is in a cystic duct.

In one embodiment the biliary duct cancer is in a common bile duct.

In one embodiment the biliary duct cancer is in an Ampulla of Vater.

In one embodiment the biliary duct cancer is a cancer of the Papilla ofVater.

There is also provided a method of treating a gallbladder cancer patientby administering a therapeutically effective amount of a compound offormula (I) an enantiomer thereof or a pharmaceutically acceptable saltof any one of the same.

Thus in one aspect there is provided use of a compound of formula (I) anenantiomer thereof or a pharmaceutically acceptable salt of any one ofthe same in the treatment of gallbladder cancer.

Also provided is a compound of formula (I) an enantiomer thereof or apharmaceutically acceptable salt of any one of the same for use in thetreatment of gallbladder cancer.

In one aspect there provided use of a compound of formula (I) anenantiomer thereof or a pharmaceutically acceptable salt of any one ofthe same for the manufacture of a medicament for the treatment ofgallbladder cancer.

In one embodiment the cancer is a metastatic form of a cancer disclosedherein.

In one embodiment the cancer according the present disclosure has notmetastasized.

In one embodiment the compound of formula (I) is(R)—N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5,-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine:

(Varlitinib) or a pharmaceutically acceptable salt thereof or a pro-drugthereof.

In one embodiment(R)—N4-[3-Chloro-4-(thiazol-2-ylmethoxy)-phenyl]-N6-(4-methyl-4,5,-dihydro-oxazol-2-yl)-quinazoline-4,6-diamine is employed/administeredas the free base (also referred to herein as Varlitinib).

Varlitinib at an appropriate dose is capable of inhibiting HER1, HER2and HER4 directly and thought to be capable of inhibiting HER3indirectly.

In one embodiment the compound of formula (I), such as Varlitinib atleast inhibits the activity of HER1 and HER2, HER1 and HER4 or HER2 andHER4.

In one embodiment the compound of formula (I) at least inhibits theactivity of HER1, HER2 and HER4, for example directly inhibits theactivity of HER1, HER2 and HER4.

In one embodiment the compound of formula (I) inhibits the activity ofHER1, HER2, HER3 and HER4, for example directly inhibits the activity ofHER1, HER2, and HER4, and indirectly inhibits the activity of HER3.

In one embodiment the compound of formula (I) an enantiomer thereof or apharmaceutically acceptable salt thereof is employed as a monotherapy,for example first line therapy or second line therapy, such as a firstline monotherapy.

In one embodiment the compound of formula (I) an enantiomer thereof or apharmaceutically acceptable salt thereof is employed in a combinationtherapy, for example in combination with a chemotherapy and/or abiological therapeutic, in particular as a first line therapy or asecond line therapy.

In one embodiment the compound of formula (I), such as Varlitinib, isemployed in combination with at least one further HER inhibitor, forexample a combination of Varlitinib and Herceptin (trastuzumab) and/orpertuzumab. Surprisingly a combination of Varlitinib and Herceptinshowed more therapeutic activity than either entity alone.

In one embodiment the compound of formula (I) such as Varlitinib isemployed in combination with ado-trastuzuma-emtansine.

In one embodiment there is provided a method of treating biliary ductcancer comprising:

a) administering a therapeutically effective amount of a compound offormula (I):

an enantiomer thereof or a pharmaceutically acceptable salt of any oneof the same, and

b) administering a chemotherapeutic agent or a combination ofchemotherapeutic agents.

In one embodiment the compound of formula (I) an enantiomer thereof or apharmaceutically acceptable salt thereof is employed as a second linemonotherapy.

Surprisingly in a second line monotherapy trial employing Varlitinib inthe treatment of cholangiocarcinoma patients showed a significantreduction in CA19-9 levels. CA19-9 is a marker employed in themanagement of cholangiocarcinoma. In a one patient a 90% reduction wasseen in CA19-9 within one month of initiating treatment with Varlitinib.

Thus in one embodiment a patient has a 10, 20, 30, 40, 50, 60, 70, 80 or90% decrease in CA19-9 level whilst on the therapy according to thepresent disclosure, wherein the level is decreased relative to the levelof CA19-9 before initiation of said therapy.

In one embodiment the compound of formula (I), such as Varlitinib, isemployed in a second line therapy together with a chemotherapy agent orchemotherapy regimen, for example gemcitabine, capecitabine, 5-FU,FOLFOX, a platin, such as cisplatin or oxaliplatin, and a combinationthereof.

In one embodiment the compound of formula (I), such as Varlitinib, isadministered orally.

In one embodiment the compound of formula (I), such as Varlitinib, isadministered at a dose in the range 100 mg to 900 mg on each occasion,in particular 200 mg, 300 mg, 400 mg or 500 mg each dose, such as 400mg, for example administered once or twice daily, such as twice daily.

In one embodiment the compound of formula (I), such as Varlitinib, isadministered for a 28 days, referred to herein as a 28 day treatmentcycle.

In one embodiment the compound of formula (I) is administered aspharmaceutical formulation comprising one or more pharmaceuticallyacceptable excipients.

In one embodiment the compound of formula (I) or a formulationcomprising the same is administered orally, for example as tablet orcapsule.

In one embodiment the target patient population is at least HER1 (EGFR)positive.

In one embodiment the target patient population is EGFR and HER2positive.

In one embodiment the target patient population is at least HER1 (EGFR)positive.

In one embodiment the target patient population are HER2 amplified.

In one embodiment the patient has over-expression of 2 or more of theHER 1, 2, 3, 4 receptors, for example over expression of HER 1 & 2; 1 &3; 1 & 4; 2 & 3 2 & 4; 1, 2 & 3; 1, 2 & 4; 2, 3 & 4; or 1, 2, 3 & 4.

In one embodiment the treatment is adjuvant therapy, for example aftersurgery or after chemotherapy.

In one embodiment the treatment is neoadjuvant therapy, for examplebefore surgery, in particular to shrink the tumour or tumours.

In one embodiment the cancer is a tumour, in particular a solid tumour.In one embodiment the treatment according to the present disclosure issuitable for the treatment of secondary tumours. In one embodiment thecancer is metastatic cancer. In one embodiment the treatment accordingto the present disclosure is suitable for the treatment of primarycancer and metastases. In one embodiment the treatment according to thepresent disclosure is suitable for the treatment of secondary cancer andmetastases. In one embodiment the treatment according to the presentdisclosure is suitable for the treatment of primary cancer, secondarycancer and metastases.

In one embodiment the treatment according to the present disclosure issuitable for the treatment of cancerous cells in a lymph node, for acancer of the present disclosure.

In one embodiment the patient is a human.

DETAILED DISCLOSURE

Biliary duct cancer (also referred to as biliary cancer) as employedherein refers to cancer which starts in the bile ducts and includescholangiocarcinoma and gallbladder cancer.

Cholangiocarcinoma as referred to herein is a form of cancer that iscomposed of mutated epithelial cells (or cells showing characteristicsof epithelial differentiation) that originate in the bile ducts whichdrain bile from the liver into the small intestine, but not includinggallbladder cancer.

General guidelines for operability include:

-   -   Absence of lymph node or liver metastases    -   Absence of involvement of the portal vein    -   Absence of direct invasion of adjacent organs    -   Absence of widespread metastatic disease

Gallbladder cancer as employed herein cancer which starts in thegallbladder. The following stages are used for gallbladder cancer:

-   -   Stage 0 (carcinoma in situ): Abnormal cells are found in the        inner (mucosal) layer of the gallbladder; these abnormal cells        may become cancer and spread into nearby normal tissue,    -   Stage I: Cancer has formed and has spread beyond the inner        (mucosal) layer to a layer of tissue with blood vessels or to        the muscle layer,    -   Stage II: Cancer has spread beyond the muscle layer to the        connective tissue around the muscle,    -   Stage IIIA: Cancer has spread through the thin layers of tissue        that cover the gallbladder and/or to the liver and/or to one        nearby organ (e.g., stomach, small intestine, colon, pancreas,        or bile ducts outside the liver),    -   Stage IIIB: Cancer has spread to nearby lymph nodes and beyond        the inner layer of the gallbladder to a layer of tissue with        blood vessels or to the muscle layer; or beyond the muscle layer        to the connective tissue around the muscle; or through the thin        layers of tissue that cover the gallbladder and/or to the liver        and/or to one nearby organ,    -   Stage IVA: Cancer has spread to a main blood vessel of the liver        or to 2 or more nearby organs or areas other than the liver.        Cancer may have spread to nearby lymph nodes.    -   Stage IVB: Cancer has spread to either lymph nodes along large        arteries in the abdomen and/or near the lower part of the        backbone or to organs or areas far away from the gallbladder.

In one embodiment the treatment of the present disclosure isneo-adjuvant therapy, for example to shrink the tumour/carcinoma beforesurgery to remove the cancerous tissue or before chemotherapy to improvethe chances of success of the latter or to reduce the severity of thetreatment required.

In one embodiment the treatment of the present disclosure is adjuvanttherapy, for example following surgery to remove the cancerous tissue.

In one embodiment the treatment of the present disclosure is adjuvanttherapy, for example following chemotherapy.

In patients where not all the cancerous tissue is removed by surgerythen the patient may benefit from adjuvant therapy which is monotherapyemploying a compound of formula (I), such as Varlitinib.

In patients where not all the cancerous tissue is removed by surgerythen the patient may benefit from combination adjuvant therapycomprising a compound of formula (I) and chemotherapy or radiotherapy.

First line therapy as employed herein is the first therapy employed forthe treatment of the cancer and in some instances the first line therapymay be neo-adjuvant therapy, in this context surgery will generally beconsidered a treatment.

Second line therapy as employed herein is treatment following first linetherapy and may be adjuvant therapy. Thus in the context of the presentspecification second line therapy is simply therapy other than firstline therapy and includes, third line therapy, fourth line therapy etc.

Monotherapy as employed herein is wherein the compound of formula (I) anenantiomer thereof and/or a pharmaceutically acceptable salt thereof, isthe only active agent being administered to the patient for thetreatment of cancer.

Combination therapy as employed herein refers to wherein the compound offormula (I) an enantiomer thereof or a pharmaceutically acceptable saltthereof is employed for the treatment of the cancer in conjunction withone or more further anticancer treatments, for example where thetreatment regimens for the two or more active anticancer agents overlapor where the two or more anticancer agents are administeredconcomitantly.

In one embodiment the combination therapy according to the presentdisclosure comprises a RON inhibitor, for example as disclosedWO2008/058229, incorporated herein by reference.

In one embodiment the combination therapy comprises a checkpointinhibitor, such as a CTLA4 inhibitor, a PD-1 inhibitor or a PD-L1inhibitor, in particular an antibody or binding fragment thereof.

Examples of pharmaceutically acceptable salts include but are notlimited to acid addition salts of strong mineral acids such as HCl andHBr salts and addition salts of strong organic acids, such as amethansulfonic acid salt, tosylates, furoates and the like, includingdi, tri salts thereof, such as ditosylates.

Analysis of patients to profile their cancer, for example to establishif their cancer is EGFR and HER2 positive is known and is routine in theart. Establishing if a cancer is HER2 amplified is also routine in theart.

Chemotherapeutic Agents

Chemotherapeutic agent and chemotherapy or cytotoxic agent are employedinterchangeably herein unless the context indicates otherwise.

Chemotherapy as employed herein is intended to refer to specificantineoplastic chemical agents or drugs that are “selectively”destructive to malignant cells and tissues, for example alkylatingagents, antimetabolites including thymidylate synthase inhibitors,anthracyclines, anti-microtubule agents including plant alkaloids,taxanes, topoisomerase inhibitors, parp inhibitors and other antitumouragents. Selectively in this context is used loosely because of coursemany of these agents have serious side effects.

The preferred dose may be chosen by the practitioner, based on thenature of the cancer being treated.

Examples of alkylating agents, which may be employed in the method ofthe present disclosure include an alkylating agent, nitrogen mustards,nitrosoureas, tetrazines, aziridines, platins and derivatives, andnon-classical alkylating agents.

Examples of platinum containing chemotherapeutic agents (also referredto as platins), include cisplatin, carboplatin, oxaliplatin,satraplatin, picoplatin, nedaplatin, triplatin and lipoplatin (aliposomal version of cisplatin), in particular cisplatin, carboplatinand oxaliplatin.

The dose for cisplatin ranges from about 20 to about 270 mg/m² dependingon the exact cancer. Often the dose is in the range about 70 to about100 mg/m².

Nitrogen mustards include mechlorethamine, cyclophosphamide, melphalan,chlorambucil, ifosfamide and busulfan.

Nitrosoureas include N-Nitroso-N-methylurea (MNU), carmustine (BCNU),lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin.Tetrazines include dacarbazine, mitozolomide and temozolomide.

Aziridines include thiotepa, mytomycin and diaziquone (AZQ).

Examples of antimetabolites, which may be employed in the method of thepresent disclosure, include anti-folates (for example methotrexate andpemetrexed), purine analogues (for example thiopurines, such asazathiopurine, mercaptopurine, thiopurine, fludarabine (including thephosphate form), pentostatin and cladribine), pyrimidine analogues (forexample fluoropyrimidines, such as 5-fluorouracil (5-FU) and prodrugsthereof such as capecitabine [Xeloda®]), floxuridine, gemcitabine,cytarabine, decitabine, raltitrexed (tomudex) hydrochloride, cladribineand 6-azauracil.

Examples of anthracyclines, which may be employed in the method of thepresent disclosure, include daunorubicin (Daunomycin), daunorubicin(liposomal), doxorubicin (Adriamycin), doxorubicin (liposomal),epirubicin, idarubicin, valrubicin currently are used only to treatbladder cancer and mitoxantrone an anthracycline analog, in particulardoxorubicin.

Examples of anti-microtubule agents, which may be employed in the methodof the present disclosure, include include vinca alkaloids and taxanes.

Vinca alkaloids include completely natural chemicals for examplevincristine and vinblastine and also semi-synthetic vinca alkaloids, forexample vinorelbine, vindesine, and vinflunine

Taxanes include paclitaxel, docetaxel, abraxane, carbazitaxel andderivatives of thereof. Derivatives of taxanes as employed hereinincludes reformulations of taxanes like taxol, for example in amicelluar formulations, derivatives also include chemical derivativeswherein synthetic chemistry is employed to modify a starting materialwhich is a taxane.

Topoisomerase inhibitors, which may be employed in a method of thepresent disclosure include type I topoisomerase inhibitors, type IItopoisomerase inhibitors and type II topoisomerase poisons. Type Iinhibitors include topotecan, irinotecan, indotecan and indimitecan.Type II inhibitors include genistein and ICRF 193 which has thefollowing structure:

Type II poisons include amsacrine, etoposide, etoposide phosphate,teniposide and doxorubicin and fluoroquinolones.

In one embodiment the chemotherapeutic is a PARP inhibitor.

In one embodiment a combination of chemotherapeutic agents employed is,for example a platin and 5-FU or a prodrug thereof, for examplecisplatin or oxaplatin and capecitabine or gemcitabine, such as FOLFOX.

In one embodiment the chemotherapy comprises a combination ofchemotherapy agents, in particular cytotoxic chemotherapeutic agents.

In one embodiment the chemotherapy combination comprises a platin, suchas cisplatin and fluorouracil or capecitabine.

In one embodiment the chemotherapy combination is capecitabine andoxaliplatin (XELOX).

In one embodiment the chemotherapy is a combination of folinic acid and5-FU, optionally in combination with oxaliplatin (FOLFOX).

In one embodiment the chemotherapy is a combination of folinic acid,5-FU and irinotecan (FOLFIRI), optionally in combination withoxaliplatin (FOLFIRINOX). The regimen, for example includes: irinotecan(180 mg/m² IV over 90 minutes) concurrently with folinic acid (400 mg/m²[or 2×250 mg/m²] IV over 120 minutes); followed by fluorouracil (400-500mg/m² IV bolus) then fluorouracil (2400-3000 mg/m² intravenous infusionover 46 hours). This cycle is typically repeated every two weeks. Thedosages shown above may vary from cycle to cycle.

In one embodiment the chemotherapy combination employs a microtubuleinhibitor, for example vincristine sulphate, epothilone A,N-[2-[(4-Hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide(ABT-751), a taxol derived chemotherapeutic agent, for examplepaclitaxel, abraxane, or docetaxel or a combination thereof.

In one embodiment the chemotherapy combination employs an mTorinhibitor. Examples of mTor inhibitors include: everolimus (RAD001),WYE-354, KU-0063794, papamycin (Sirolimus), Temsirolimus, Deforolimus(MK-8669), AZD8055 and BEZ235 (NVP-BEZ235).

In one embodiment the chemotherapy combination employs a MEK inhibitor.Examples of MEK inhibitors include: AS703026, CI-1040 (PD184352),AZD6244 (Selumetinib), PD318088, PD0325901, AZD8330, PD98059,U0126-EtOH, BIX 02189 or BIX 02188.

In one embodiment the chemotherapy combination employs an AKT inhibitor.Examples of AKT inhibitors include: MK-2206 and AT7867.

In one embodiment the combination employs an aurora kinase inhibitor.Examples of aurora kinase inhibitors include: Aurora A Inhibitor I,VX-680, AZD1152-HQPA (Barasertib), SNS-314 Mesylate, PHA-680632,ZM-447439, CCT129202 and Hesperadin.

In one embodiment the chemotherapy combination employs a p38 inhibitor,for example as disclosed in WO2010/038086, such asN-[4-({4-[3-(3-tert-Butyl-1-p-tolyl-1H-pyrazol-5-yl)ureido]naphthalen-1-yloxy}methyl)pyridin-2-yl]-2-methoxyacetamide.

In one embodiment the combination employs a Bcl-2 inhibitor. Examples ofBcl-2 inhibitors include: obatoclax mesylate, ABT-737, ABT-263(navitoclax) and TW-37.

In one embodiment the chemotherapy combination comprises anantimetabolite such as capecitabine (xeloda), fludarabine phosphate,fludarabine (fludara), decitabine, raltitrexed (tomudex), gemcitabinehydrochloride and/or cladribine.

In one embodiment the chemotherapy combination comprises ganciclovir,which may assist in controlling immune responses and/or tumourvasculation.

In one embodiment after combination therapy a monotherapy comprising acompound of formula (I), such as Varlitinib (as defined herein includingdoses described above) is employed, for example a maintenance therapy.

“Comprising” in the context of the present specification is intended tomean “including”. Where technically appropriate, embodiments of theinvention may be combined.

Embodiments are described herein as comprising certainfeatures/elements. The disclosure also extends to separate embodimentsconsisting or consisting essentially of said features/elements.

Technical references such as patents and applications are incorporatedherein by reference.

Any embodiments specifically and explicitly recited herein may form thebasis of a disclaimer either alone or in combination with one or morefurther embodiments.

The invention will now be described with reference to the followingexamples, which are merely illustrative and should not in any way beconstrued as limiting the scope of the present invention.

BRIEF SUMMARY OF THE FIGURES

FIG. 1 Shows the position of bile ducts in the body

FIG. 2 Shows data for a cholangiocarcinoma patient receiving 400 mg ofVarlitinib monotherapy bi-daily

FIG. 3 Shows data for a cholangiocarcinoma patient receiving 400 mgVarlitinib bi-daily in combination with chemotherapy.

FIG. 4 Shows data for a 56 year old male cholangiocarcinoma patienttreated with Varlitinib 400 mg bi-daily and cisplatin/capecitabinechemotherapy

FIG. 5 Shows data for a 60 year old male cholangiocarcinoma patienttreated with Varlitinib 500 mg bi-daily and cisplatin/capecitabinechemotherapy

FIG. 6a Shows change in a lesion of over time for individualcholangiocarcinoma patients receiving between 300 and 500 mg ofVarlitinib bi-daily and chemotherapy in a Taiwanese clinical trial

FIG. 6b Shows change in a lesion of over time for individualcholangiocarcinoma patients receiving between 300 and 500 mg ofVarlitinib bi-daily and chemotherapy in a Singapore clinical trial

FIG. 7a Shows the maximal % change in tumour size from baseline inindividual cholangiocarcinoma patients receiving between 300-500 mg ofVarlitinib bi-daily and chemotherapy in Taiwan clinical trial

FIG. 7b Shows the maximal % change in tumour size from baseline inindividual cholangiocarcinoma patients receiving between 300-500 mg ofVarlitinib bi-daily and chemotherapy in Taiwan clinical trial

EXAMPLES Example 1 Varlitinib 400 mg Bi-Daily Monotherapy

A 45 year-old male stage IV cholangiocarcinoma EGFR positive (3+) cancerpatient had progressive disease following:

-   -   first line treatment with gemcitabine (partial remission), and        second line treatment with cisplatin and 5-FU.

The results are shown in FIG. 2. After treatment cycle 6 with Varlitinib400 mg bi-daily the liver tumours decreased in size up to 23% and thetumour marker CA 19-9 fell from ˜900 U/ml to ˜250 U/ml.

Example 2 Varlitinib 400 mg Bi-Daily Monotherapy

A 58 year-old, male, stage IV, extra-hepatic cholangiocarcinoma, priortreatment:

-   -   Whipple    -   Radiotherapy    -   Gemzar/cisplatin for 6 months

For the first 6 cycles, the patient received Varlitinib 400 mg BIDcontinuously with cisplatin (80 mg/m² every 3 weeks) and capecitabine(1000 mg/m2 BID, 2 weeks on, 1 week off). Image scan at the end of cycle6 showed 85.77% reduction in tumour size. After cycle 6, the patientreceived varlitinib monotherapy and tumor scan at the end of cycle 8showed 87% reduction.

This patient showed partial remission for 24 weeks. However, at the endof cycle 10, image scan showed tumour enlarged to the extent that metcriteria for disease progression based on RECIST (>20% increase againstnadir), so the patient was withdrawn from this study. In summary, thepatient received varlitinib with chemo for 6 cycles and varlitinibmonotherapy for another 4 cycles (3 weeks per cycle).

The results are shown in FIG. 3.

Example 3 Treatment of Cholangiocarcinoma with Varlitinib 400 mgBi-Daily Orally and Cisplatin/Capecitabine Combination Chemotherapy

A 56 year-old male with stage IV cholangiocarcinoma (3 lesions) hadprogressive disease following treatment with:

-   -   radiotherapy, and    -   gemcitabine (Gemzar®) and cisplatin-6 months.

After treatment cycle 6 with Varlitinib 400 mg bi-daily, cisplatin andcapecitabine the patient showed an 85.77% response, see FIG. 4. No doselimiting toxicity was observed in the first two treatment cycles.Varlitinib was well tolerated. The cisplatin and capecitabine regime wascisplatin 80 mg/m² IV infusion and capecitabine 1000 mg/m² orally twicedaily for 14 days every 3 weeks.

Example 4 Treatment of Cholangiocarcinoma with Varlitinib 500 mgBi-Daily Orally and Cisplatin/Capecitabine Combination Chemotherapy

A 60 year-old male with stage IV cholangiocarcinoma had progressivedisease following treatment with radiotherapy and bi-weekly 5-FU.

After treatment cycle 2 with Varlitinib orally 500 mg bi-daily,cisplatin and capecitabine the patient showed a 4% response, see FIG. 5.The cisplatin and capecitabine regime was cisplatin 80 mg/m² IV infusionand capecitabine 1000 mg/m² orally twice daily for 14 days every 3weeks.

Example 5 Treatment of Stage IV Cholangiocarcinoma and MetastaticLymphadenopathy with Varlitinib 400 mg Bi-Daily Orally and Cisplatin/5FUCombination Chemotherapy

A 49 year-old male was diagnosed with stage IV cholangiocarcinoma andmetastatic lymphadenopathy in January 2016. No prior surgery ortreatment was given before initiating first line treatment of 300 mg BIDVarlitinib combined with Cisplating/5-FU, 28-day treatment cycle.

Date of the first response 5 Mar. 2016, tumor C2 was reduced by 16%.Last response tumor C4 was reduced by 13% (17 May 2016). Patient currentdisease status is stable disease.

Example 6 Treatment of the Intrahepatic Bile Duct Cholangiocarcinomawith 300 mg Valitinib and FOLFOX

A 51 year old female diagnosed in 2013 with intrahepatic bile ductcholangiocarcinoma, had received surgery in the form of lefthemihepatectomy in 15 Jul. 2013. Prior therapies were gemcitabine andcisplatin (in the period 14 Aug. 2013 to 8 Jan. 2014) and repeatedbetween 13 May 2015 and 1 Jul. 2015. With this treatment the status wasprogressive disease. The patient was given 9 cycles of a combination ofVarlitinib 400 mg reduced to 300 mg BID and FOLFOX. This was followedwith 7 cycles of Varlitinib monotherapy. The patient status is partialresponse with a reduction is tumor size of 50%.

Example 7 Treatment of Stage IV Cholangiocarcinoma with Varlitinib 400mg Bi-Daily Orally and Cisplatin/5FU Combination Chemotherapy

A 69 year-old female with stage IV cholangiocarcinoma newly diagnosed in2014 received surgery (percutaneous transhepatic cholangial drainage andtranscatheter anterior embolization), followed by adjuvant treatment ofVarlitinib 400 mg BID combined with cisplatin s/5-FU 28-day cycle. Aftercycle 6 (14 Jul. 2015), only 400 mg BID Varlitinib was taken. Patientcompleted 10 cycles of monotherapy. At Cycle 11 Day 1, dose was reducedto 300 mg BID alternate days. First response was observed in cycle 2 oftreatment 17 Mar. 2015. Progressive disease observed in cycle 16 ofmonotherapy 12 Apr. 2016. This patient demonstrated remarkable diseasecontrol on varlitinib monotherapy after 6 cycles of varlitinib incombination with chemotherapy.

Example 8 Treatment of Stage IV Intrahepatic Cholangiocarcinoma withVarlitinib 400 mg Bi-Daily Orally and FOLFOX

A 51 year-old female who had a medical history of meningioma postexcision with left craniotomy was diagnosed with intrahepaticcholangiocarcinoma, stage IV with metastasis to portacaval lymph nodesand liver in August 2014. She received left hemihepatectomy followed by6 cycles of adjuvant gemcitabine and cisplatin. The patient's diseaseprogressed in May 2015 and she received 1st line gemcitabine andcisplatin in metastatic setting, to which he did not respond. Afterdisease progression on gemcitabine and cisplatin, she was enrolled intothe ASLAN001-002SG study in August 2015 and received Varlitinib 400 mgBID in combination with mFOLFOX6 (2 weeks per cycle). To date (22 Aug.2016), the patient has completed 9 cycles of Varlitinib and mFOLFOX6, aswell as, 9 cycles of varlitinib monotherapy and the latest tumorassessment completed after cycle 18 continues to show partial responsewith 53% reduction in tumor size as the best response from baseline.

Example 9 Treatment of Stage IV Intrahepatic Cholangiocarcinoma andMultiple Lymphadenopathies with Varlitinib 300 mg Bi-Daily Orally andCisplatin/5FU Combination Chemotherapy 28 Day Cycle

A 64 year old female diagnosed with intrahepatic cholangiocarcinoma andmultiple lymphadenopathies in May 2016 received Varlitinib combinationtherapy as the first line treatment.

The patient was given 300 mg BID Varlitinib combined with Cis/5-FU,28-day cycle. The current status is the clinical trial is on-going.

1. A method of treating a biliary duct cancer by administering atherapeutically effective amount of a compound of formula (I):

an enantiomer thereof or a pharmaceutically acceptable salt of any oneof the same; wherein the biliary duct cancer is gallbladder cancer orcholangiocarcinoma; and wherein the cholangiocarcinoma is located in anintrahepatic bile duct, left hepatic duct, right hepatic duct, commonhepatic duct, cystic duct, common bile duct, Ampulla of Vater or anycombinations thereof. 2.-4. (canceled)
 5. A method according to claim 1,wherein the cholangiocarcinoma is intrahepatic.
 6. A method according toclaim 1, wherein the cholangiocarcinoma is extrahepatic.
 7. A methodaccording to claim 1, wherein the compound of formula (I) is Varlitinib:

or a pharmaceutically acceptable salt thereof.
 8. A method according toclaim 1, wherein the compound of formula (I) is provided as the freebase.
 9. A method according to claim 1, wherein the compound of formula(I) is administered as a pharmaceutical formulation.
 10. A methodaccording to claim 1, wherein the compound of formula (I) or apharmaceutical formulation comprising same is administered orally.
 11. Amethod according to claim 1, wherein the compound of formula (I) or apharmaceutical formulation comprising the same is administered bi-daily.12. A method according to claim 1, wherein each dose of the compound offormula (I) is in the range 100 to 900 mg.
 13. A method according toclaim 12, wherein each dose of the compound of formula (I) is in therange 300 to 500 mg.
 14. A method according to claim 13, wherein eachdose is 400 mg.
 15. A method according to claim 1, wherein the compoundof formula (I) or formulation comprising the same is employed as amonotherapy.
 16. A method according to claim 1, wherein the compound offormula (I) is employed in a combination.
 17. A method according toclaim 16, wherein the combination therapy comprises Herceptin and/orpertuzumab.
 18. A method according to claim 16, wherein the combinationtherapy comprise ado-trastuzumab.
 19. A method according to claim 16wherein the combination therapy comprises a chemotherapeutic agent. 20.A method according to claim 19, wherein the chemotherapeutic agent isindependently from the group comprising a platin (such as cisplatin oroxaliplatin), gemcitabine, capecitabine, 5-FU, FOLFOX, FOLFIRI andFOLFIRINOX.
 21. A compound of formula (I) as disclosed in claim 1, foruse in the treatment of biliary duct cancer.
 22. Use of a compound offormula (I) as disclosed in claim 1, for the manufacture of a medicamentfor the treatment of biliary cancer.